SUMMARY/ABSTRACT Hyperandrogenism combined with obesity are clinical hallmarks of polycystic ovary syndrome (PCOS), a complex disorder affecting ~10% of reproductive-aged women. Many women with androgen excess (AE) also display ?metabolic syndrome? with insulin resistance, hyperinsulinemia, and impaired glucose tolerance. These women often have subfertility associated with menstrual cycle irregularities. Even in women with normal cycles, AE and metabolic syndrome correlate with impaired endometrial and placental function leading to poor reproductive outcome. In this NCTRI center, we will interrogate the actions and interactions of AE and diet on reproductive health with the goal of improving fertility in women with AE and metabolic syndrome. Our premise is that AE and/or exposure to an obesogenic diet, disrupts endometrial and placental physiology. To discern the actions and interactions of AE and diet on reproductive function, we are chronically treating young female macaques with mildly elevated testosterone (T), in the presence or absence of an obesogenic western-style diet (WSD). Our intent is to mimic the conditions in adolescent girls at risk for developing PCOS. We report that after 3-4 years of treatment, the T and T + WSD groups exhibit impaired ovarian and endometrial function, attenuated placental vascular perfusion, and reduced pregnancy rate. These animals are now being treated for 5 years. Our hypothesis is that continued exposure to T and/or WSD will further deteriorate uterine and placental function and exacerbate the effect on reproductive success. To test this hypothesis, we will continue treatment for an additional year and conduct longitudinal studies on endometrial/placental function and fertility. The treatments will then be stopped, and we will test the hypothesis that treatment removal restores uterine/placental phenotype and fertility. Our specific aims are: 1) To characterize the long-term effect of T and/or WSD on endometrial morphology, markers of endometrial receptivity, placental function, and metabolism; 2) To utilize contrast-enhanced ultrasound imaging (CEUS) to identify vascular compromise in the endometrium and placenta associated with T and/or WSD; 3) To determine whether T and/or WSD exacerbates inflammation in the endometrium and placenta using in vivo molecular detection of inflammation by CEUS, and correlating it to immunohistological markers; and, 4) To determine if withdrawal of T and WSD treatments returns the endometrium to a normal pre-implantation phenotype, and restores placental physiology leading to normal reproductive outcome. Results of this research will be correlated with metabolic and ovarian effects identified in NCTRI projects I and II.